The present invention is broadly directed to a device for the controlled release of an active substance into a fluid medium at a substantially constant (i.e., zero-order) rate over an appreciable or prolonged time interval. Said device comprises said substance homogeneously disposed and contained substantially in the shape of a truncated cone by means of an impermeable wall or coating on the base and side (but not the top) of said cone. When the device is a partially coated tablet, particularly a tablet comprising a pharmaceutically effective agent for oral use in a mammal, the present invention is also directed to a tablet press for use in the manufacture of a tablet substantially in the shape of said truncated cone, and (after fully coating such tablets by conventional means) to an apparatus for removal of the tablet coating from the top (i.e., smaller diameter end) of the tablets.
A readily manufactured device which will dependably release an active material (e.g., a pharmaceutical agent, a cleanser or a deodorizer) at a zero-order rate into a fluid medium (gaseous or liquid) has remained an elusive goal, particularly when the device is in the form of a tablet for controlled in vivo release of a pharmaceutical agent into a biological fluid (e.g., the fluid of the gastrointestinal tract).
An early proposed method was that of Jacobs, U.S. Pat. No. 3,113,076 (1963) in which the drug was combined in a suitable carrier and tablets obtained by an extrusion method. The principle was to form tablets with approximately equal outer and "inner" surfaces, the latter accessed by aperture(s). As the exterior surface is dissolved, the area decreases, while as the inner surface dissolves, the surface area increases. Absent diffusion effects respecting the interior surface, the total surface, and thus rate of solution, would remain relatively constant. In its simplest form, Jacobs' tablet is a cylinder achieving equal inner surface by a multiplicity of cylindrical holes which are parallel to the axis of the outer cylinder, and accessed by the multiple apertures at each end of the cylinder. A related, but more sophisticated device, which now takes into account diffusion effects with respect to the inner surfaces, is that of Brooke, U.S. Pat. No. 3,851,648 (1974). Brooke discloses a cylindrical container, closed at the ends, with a cavity in the shape of a cylinder sector with the aperture in the form of a slot in the outer surface of cylinder (parallel to the axis of the cylinder), said slot at the apex of the cylinder sector cavity. See also Brooke et al., J. Pharm. Sci. 66, pp. 159-162 (1977). In practice, this device produces release rates which are initially high; Lipper et al., J. Pharm. Sci. 66, pp. 163-164 (1977). It is suggested that the device might be implanted into body cavities, but there is no suggestion for use of this device in the form of an ordinary tablet, or for a method of manufacturing such a tablet.
Langer et al., A.I.Ch.E. Symposium Series, No. 206, vol. 77, pp. 10-20 (1981) analyzed several geometries for approaching zero-order release kinetics; a slab (open in one of its major faces; a coated half-cylinder with a parallel, half-cylinder opening in its flat face; and a coated hemisphere with a small, open concavity in the center of its flat face. Only the latter provides predicted release rates close to zero-order, although even here an initially faster release is predicted, a result shown in practice by Hsieh et al., J. Pharm. Sci. 72, pp. 17-22 (1983) for release of sodium salicylate. Hsieh et al. propose a method for fabrication of such hemispheric devices in tablet form by initially molding a mixture of the drug and polymeric carrier, inserting a stick or bead into the center of the flat face, coating and finally removing the stick or bead from the face to form the small concavity. Such a method is hardly amenable to high speed tablet manufacture. Even without such methods, major problems were encountered by Hsieh et al. in this fabrication method, both in the techniques of coating and in uniformly opening the cavity.
Various types of boluses, for the relatively long term release of an active agent in the rumen or reticulum of a ruminant mammal, based on designs similar to those for tablets as discussed above, are also found in the prior art. See, for example, Dresback, U.S. Pat. No. 4,220,152 (1980), Cardinal, U.S. Pat. No. 4,601,893 (1986) and Guerrero et al., U.K. Patent Appln. No. 2,077,103 (1980).
More recently, Lai et al., Abstract No. 133, A.Ph.A. Meeting, Oct. 21-24, 1985, derived mathematical diffusional models for drug release from various geometries including "a hemisphere with a dimple-shaped releasing surface" (presumably as described above) and "a truncated cone and a tapered cylinder with central releasing hole". No actual or suggested preparation of such tablets is indicated, nor is any possible advantage suggested for the truncated cone over the coated hemisphere described above.